PROJECT SUMMARY Opioid use disorder (OUD) is a major public health crisis in the United States, with >50,000 overdose deaths in 2017 alone. Addiction to opioids is intimately related to the physiology of the brain?s dopamine-based rewarding system. The neurotensin 1 receptor (NTR1) is found among dopamine pre and post-synaptic neurons in the central nervous system, and acts as a modulator of dopaminergic systems. Even though substantial evidence points towards NTR1 as a molecular target for treating addiction disorders, few non- peptide brain penetrant neurotensin modulators have been identified, and orthosteric NTR1 ligands display side effects including hypotension and hypothermia that have limited their clinical development. Recently, we have discovered a series of brain-penetrant NTR1 modulators, including a lead compound SBI-553, with a unique mechanism of action at NTR1. SBI-553 is an orally available and brain penetrant b-arrestin biased allosteric modulator of NTR1, which shows efficacy in a range of addiction models. The literature contains no documented reports of such molecules among positive or negative allosteric modulators of GPCRs. In addition, the unique profile of SBI-553 appears to circumvent the clinically limiting side effects of hypothermia and hypotension displayed by orthosteric NTR1 ligands. While potentially high risk, the activity of SBI-553 has been validated in vitro and in vivo, and the initial safety profiling indicates no issues that would preclude further development. The goal of the application is to develop SBI-553 as a treatment for opioid use disorders. A 2-year UG3 phase is proposed with the primary objective of determining the suitability of SBI-553 (or a backup compound) entering IND-enabling studies followed by a 2-year UH3 phase with the primary objective of completing a Phase 1 single ascending dose study. During the UG3 phase, the team will complete pharmacokinetic (PK) studies and the preclinical safety profile of SBI-553 in a relevant species; identify a backup compound to SBI-553; and conduct definitive cellular and in vivo pharmacology studies with SBI-553 (and/or potential backup) in models of addiction to inform best clinical indication and clinical endpoints (PK/pharmacodynamic). During the UH3 Phase, the team will ensure completion of GMP Synthesis, Stability Testing and Formulation; GLP Toxicology studies; and the Phase 1 single ascending dose study.